High expression levels of IKKα and IKKβ are necessary for the malignant properties of liver cancer
High expression levels of IKKα and IKKβ are necessary for the malignant properties of liver cancer
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DOI：
10.1002/ijc.24854
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发表时间：
2010-03-01
影响因子：
6.4
通讯作者：
Sun, Beicheng
中科院分区：
文献类型：
--
作者：
Jiang, Runqiu;Xia, Yongxiang;Sun, Beicheng
IKK-NF-kappaB信号转导被认为是肝癌发生的重要因素，也是肝癌治疗的潜在靶点。因此，本研究采用实时定量聚合酶链式反应技术检测了40例肝癌组织中核因子-kappaB信号转导元件和靶基因的表达，包括IKKα、IKKβ、RANKL、OPG、细胞周期蛋白D3、乳腺丝氨酸蛋白酶抑制因子、细胞周期蛋白D1、c-Flip、Bclx1、STAT3、Cip1和Cip2。经统计学分析，7项指标：IKKα、IKKβ、RANK、Maspin、c-Flip、Cip2和Cyclin D1在肿瘤组织和相应癌旁组织之间有显著差异。当IKKα和IKKβ在体外表达下调时，IKKα和IKKβ基因敲除的肝癌细胞系中BrdU阳性细胞数均减少。同时研究了IKKα基因敲除细胞和IKKβ基因敲除细胞的凋亡水平。皮下移植模型抑制了肝癌的生长，肾包膜移植模型也显著抑制了肺转移。体外培养的肝癌细胞中IKKα和IKKβ的表达下调，提示Maspin、OPG和RANKL的表达增加与肝癌的转移有关。这些发现可能与bclxl和c-flip表达下调有关，这可能是细胞凋亡率增加的原因。IKKα和IKKβ下调的治疗效果取决于核因子-kappaB的抑制程度和肝细胞癌的恶性程度。我们预计IKK靶向基因治疗可以用于治疗肝癌，这是一种出了名的对放射和化疗耐药的癌症。
IKK-NF-kappa B signaling is regarded as an important factor in hepatocarcinogenesis and a potential target for liver cancer therapy. Therefore, in this study, we analyzed the expression of mRNAs encoding components and targets of NF-kappa B signaling including IKK alpha, IKK beta, RANK, RANKL, OPG, CyclinD3, mammary serine protease inhibitor (Maspin), CyclinD1, c-FLIP, Bcl-x1, Stat3, Cip1 and Cip2 by real-time PCR in 40 patients with liver cancer. After statistical analysis, 7 indices including IKK alpha, IKK beta, RANK, Maspin, c-FLIP, Cip2 and cyclinD1 were found to show significant differences between tumor tissue and its corresponding adjacent tissue. When IKK alpha and IKK beta were downregulated in the hepatocellular carcinoma (HCC) cell lines of MHCC-97L and MHCC-97H in vitro, the numbers of BrdU positive cells were decreased in both IKK alpha and IKK beta knockdown cells. Levels of apoptosis were also investigated in IKK alpha and IKK beta knockdown cells. The growth of HCC was inhibited in the subcutaneous implantation model, and lung metastatogenesis was also significantly inhibited in the kidney capsule transplantation model. Downregulation of IKK alpha and IKK beta in HCC cultured in vitro revealed that increased Maspin, OPG and RANKL expression was associated with metastasis of HCC. These findings were associated with downregulation of Bcl-XL and c-FLIP, which may be the reason for increased apoptosis. The therapeutic effect of IKK alpha and IKK beta downregulation depends on extent of NF-kappa B inhibition and the malignant nature of the HCC. We anticipate that IKK-targeted gene therapy can be used in the treatment of HCC, a cancer that is notoriously resistant to radiation and chemotherapy.